The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model

Vaishali Kakkar; Cecilia Månsson; Eduardo P. de Mattos; Steven Bergink; Marianne van der Zwaag; Maria A.W.H. van Waarde; Niels J. Kloosterhuis; Ronald Melki; Remco T.P. van Cruchten; Salam Al-Karadaghi; Paolo Arosio; Christopher M. Dobson; Tuomas P.J. Knowles; Gillian P. Bates; Jan M. van Deursen; Sara Linse; Bart van de Sluis; Cecilia Emanuelsson; Harm H. Kampinga

doi:10.1016/j.molcel.2016.03.017

The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model

Vaishali Kakkar, Cecilia Månsson, Eduardo P. de Mattos, Steven Bergink, Marianne van der Zwaag, Maria A.W.H. van Waarde, Niels J. Kloosterhuis, Ronald Melki, Remco T.P. van Cruchten, Salam Al-Karadaghi, Paolo Arosio, Christopher M. Dobson, Tuomas P.J. Knowles, Gillian P. Bates, Jan M. van Deursen, Sara Linse, Bart van de Sluis, Cecilia Emanuelsson, Harm H. Kampinga

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Abstract

Summary Expanded CAG repeats lead to debilitating neurodegenerative disorders characterized by aggregation of proteins with expanded polyglutamine (polyQ) tracts. The mechanism of aggregation involves primary and secondary nucleation steps. We show how a noncanonical member of the DNAJ-chaperone family, DNAJB6, inhibits the conversion of soluble polyQ peptides into amyloid fibrils, in particular by suppressing primary nucleation. This inhibition is mediated by a serine/threonine-rich region that provides an array of surface-exposed hydroxyl groups that bind to polyQ peptides and may disrupt the formation of the H bonds essential for the stability of amyloid fibrils. Early prevention of polyQ aggregation by DNAJB6 occurs also in cells and leads to delayed neurite retraction even before aggregates are visible. In a mouse model, brain-specific coexpression of DNAJB6 delays polyQ aggregation, relieves symptoms, and prolongs lifespan, pointing to DNAJB6 as a potential target for disease therapy and tool for unraveling early events in the onset of polyQ diseases.

Original language	English
Journal	MOLECULAR CELL
Early online date	14 Apr 2016
DOIs	https://doi.org/10.1016/j.molcel.2016.03.017
Publication status	E-pub ahead of print - 14 Apr 2016

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Kakkar, V., Månsson, C., de Mattos, EP., Bergink, S., van der Zwaag, M., van Waarde, MA. W. H., Kloosterhuis, NJ., Melki, R., van Cruchten, RT. P., Al-Karadaghi, S., Arosio, P., Dobson, CM., Knowles, TP. J., Bates, G. P., van Deursen, J. M., Linse, S., van de Sluis, B., Emanuelsson, C., & Kampinga, HH. (2016). The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model. MOLECULAR CELL. Advance online publication. https://doi.org/10.1016/j.molcel.2016.03.017

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title = "The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model",

abstract = "Summary Expanded CAG repeats lead to debilitating neurodegenerative disorders characterized by aggregation of proteins with expanded polyglutamine (polyQ) tracts. The mechanism of aggregation involves primary and secondary nucleation steps. We show how a noncanonical member of the DNAJ-chaperone family, DNAJB6, inhibits the conversion of soluble polyQ peptides into amyloid fibrils, in particular by suppressing primary nucleation. This inhibition is mediated by a serine/threonine-rich region that provides an array of surface-exposed hydroxyl groups that bind to polyQ peptides and may disrupt the formation of the H bonds essential for the stability of amyloid fibrils. Early prevention of polyQ aggregation by DNAJB6 occurs also in cells and leads to delayed neurite retraction even before aggregates are visible. In a mouse model, brain-specific coexpression of DNAJB6 delays polyQ aggregation, relieves symptoms, and prolongs lifespan, pointing to DNAJB6 as a potential target for disease therapy and tool for unraveling early events in the onset of polyQ diseases.",

author = "Vaishali Kakkar and Cecilia M{\aa}nsson and Eduardo P. de Mattos and Steven Bergink and Marianne van der Zwaag and Maria A.W.H. van Waarde and Niels J. Kloosterhuis and Ronald Melki and Remco T.P. van Cruchten and Salam Al-Karadaghi and Paolo Arosio and Christopher M. Dobson and Tuomas P.J. Knowles and Bates, {Gillian P.} and van Deursen, {Jan M.} and Sara Linse and Bart van de Sluis and Cecilia Emanuelsson and Harm H. Kampinga",

year = "2016",

month = apr,

day = "14",

doi = "10.1016/j.molcel.2016.03.017",

language = "English",

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issn = "1097-2765",

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Kakkar, V, Månsson, C, de Mattos, EP, Bergink, S, van der Zwaag, M, van Waarde, MAWH, Kloosterhuis, NJ, Melki, R, van Cruchten, RTP, Al-Karadaghi, S, Arosio, P, Dobson, CM, Knowles, TPJ, Bates, GP, van Deursen, JM, Linse, S, van de Sluis, B, Emanuelsson, C & Kampinga, HH 2016, 'The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model', MOLECULAR CELL. https://doi.org/10.1016/j.molcel.2016.03.017

TY - JOUR

T1 - The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model

AU - Kakkar, Vaishali

AU - Månsson, Cecilia

AU - de Mattos, Eduardo P.

AU - Bergink, Steven

AU - van der Zwaag, Marianne

AU - van Waarde, Maria A.W.H.

AU - Kloosterhuis, Niels J.

AU - Melki, Ronald

AU - van Cruchten, Remco T.P.

AU - Al-Karadaghi, Salam

AU - Arosio, Paolo

AU - Dobson, Christopher M.

AU - Knowles, Tuomas P.J.

AU - Bates, Gillian P.

AU - van Deursen, Jan M.

AU - Linse, Sara

AU - van de Sluis, Bart

AU - Emanuelsson, Cecilia

AU - Kampinga, Harm H.

PY - 2016/4/14

Y1 - 2016/4/14

N2 - Summary Expanded CAG repeats lead to debilitating neurodegenerative disorders characterized by aggregation of proteins with expanded polyglutamine (polyQ) tracts. The mechanism of aggregation involves primary and secondary nucleation steps. We show how a noncanonical member of the DNAJ-chaperone family, DNAJB6, inhibits the conversion of soluble polyQ peptides into amyloid fibrils, in particular by suppressing primary nucleation. This inhibition is mediated by a serine/threonine-rich region that provides an array of surface-exposed hydroxyl groups that bind to polyQ peptides and may disrupt the formation of the H bonds essential for the stability of amyloid fibrils. Early prevention of polyQ aggregation by DNAJB6 occurs also in cells and leads to delayed neurite retraction even before aggregates are visible. In a mouse model, brain-specific coexpression of DNAJB6 delays polyQ aggregation, relieves symptoms, and prolongs lifespan, pointing to DNAJB6 as a potential target for disease therapy and tool for unraveling early events in the onset of polyQ diseases.

AB - Summary Expanded CAG repeats lead to debilitating neurodegenerative disorders characterized by aggregation of proteins with expanded polyglutamine (polyQ) tracts. The mechanism of aggregation involves primary and secondary nucleation steps. We show how a noncanonical member of the DNAJ-chaperone family, DNAJB6, inhibits the conversion of soluble polyQ peptides into amyloid fibrils, in particular by suppressing primary nucleation. This inhibition is mediated by a serine/threonine-rich region that provides an array of surface-exposed hydroxyl groups that bind to polyQ peptides and may disrupt the formation of the H bonds essential for the stability of amyloid fibrils. Early prevention of polyQ aggregation by DNAJB6 occurs also in cells and leads to delayed neurite retraction even before aggregates are visible. In a mouse model, brain-specific coexpression of DNAJB6 delays polyQ aggregation, relieves symptoms, and prolongs lifespan, pointing to DNAJB6 as a potential target for disease therapy and tool for unraveling early events in the onset of polyQ diseases.

U2 - 10.1016/j.molcel.2016.03.017

DO - 10.1016/j.molcel.2016.03.017

M3 - Article

SN - 1097-2765

JO - MOLECULAR CELL

JF - MOLECULAR CELL

ER -

The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model

Abstract

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